Topoisomerase I (Top1) is an enzyme that is believed to relax supercoiled DNA. Relaxed DNA is reported to be required for many cellular processes such as DNA replication, transcription, and repair. Top1 is believed to relax DNA through a cycle of cleavage and religation steps involving the active site residue Tyr723. This residue is believed to attack the phosphodiester backbone, breaking the single strand and forming a covalent “cleavage complex” in which the unbroken strand undergoes “controlled rotation” and relaxes the DNA. After relaxation, the scissile strand is believed to be religated and the enzyme is released. As inhibition of Top1 is believed to be capable of leading to cell death, several Top1 inhibitors have been reportedly developed as a targeted approach for anti-cancer therapy. Camptothecin (1) and its clinically used analogues, topotecan (2) and irinotecan (3), were reported to inhibit Top1 activity by intercalating into the cleavage complex and preventing the religation step of the catalytic cycle. As a result, it is believed that advancing replication forks collide with the cleavage complex, resulting in double-stranded DNA breaks and apoptosis. Compounds that inhibit the religation reaction are commonly known as “Top1 poisons”.
